Because it is difficult to predict which primary tumors will progress to regional or distant metastases, cutaneous melanoma remains a challenging disease to manage (1). New strategies for the identification of epigenetic biomarkers may improve the clinical management of melanoma by facilitating earlier disease diagnosis and providing more accurate prognostic information. No major study has examined the epigenetic alterations of hormone receptors in the progression from primary to metastatic melanoma in a large series of patients.
Hypermethylation of gene promoter CpG islands plays a significant role in the development and progression of various cancers, including melanoma (2-6). The identification of hypermethylated genes in tumors has become an accepted approach to assess tumor-related gene inactivation (6-9). Tumor-related gene hypermethylation in primary and metastatic melanomas was previously reported (10). Thereafter, the hypermethylation of multiple tumor-related and tumor suppressor genes during progression from primary to metastatic lesions was demonstrated (11). Several genes methylated in primary and metastatic melanomas were also detected in serum as methylated circulating DNA (11). The observation that tumor-related DNA could be detected in circulating serum provided a method of disease surveillance independent of the availability of gross tumor tissue (12-17).
ER-α belongs to a superfamily of transcription activators (18, 19) involved in many physiological processes, including tumor progression (20-22). Loss of ER-α expression has been associated with aberrant CpG island hypermethylation in breast cancer cell lines and tumors (23-27), and shown to modulate breast cancer progression (5). Several studies have reported the presence of estrogen receptor in melanoma cell lines, but analysis of human melanomas have shown variable ER-α expression (28-31). Several in vitro experiments established that tamoxifen is an effective growth inhibitor of melanoma cells (32, 33). Based on the variable presence of ER-α in melanoma cells, as well as anecdotal reports of clinical responses to anti-estrogen therapy, several studies of hormonal and chemohormonal treatments were coordinated. Initial trials were encouraging, with improved response rates and median overall survival in patients, receiving tamoxifen, particularly women (34, 35). Subsequent trials, however, failed to show significant differences in response rates or overall survival when tamoxifen was used alone or in combination with systemic therapies (36-42). Reasons for the discrepancies in response to anti-estrogen therapy between these trials are unknown.